1. Field of the Invention
This invention is directed to novel succinate compounds. This invention is also directed to uses of these compounds in various medicinal applications, including treating disorders amenable to treatment by peptidyl deformylase inhibitors. This invention is still further directed to pharmaceutical compounds comprising these compounds and methods of synthesis thereof.
2. State of the Art
Treatment of microbial infection in host organisms requires an effective means to kill the microbe while doing as little harm to the host as possible. Accordingly, agents which target characteristics unique to a pathology-causing microorganism are desirable for treatment. Penicillin is an extremely well known example of such an agent. Penicillin acts by inhibiting biosynthesis of bacterial cell walls. Since mammalian cells do not require cell walls for survival, administration of penicillin to a human infected with bacteria can kill the bacteria without killing human cells.
However, the use of antibiotics and antimicrobials has also resulted in increased resistance to these agents. As bacteria become resistant to older, more widely used antimicrobial agents, new antimicrobials must be developed in order to provide effective treatments for human and non-human animals suffering from microbial infection.
Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (Chang et al. J. Bacteriol. 171:4071-4072 (1989); Meinnel T, Blanquet S, J. Bacteriol. 176(23):7387-90 (1994); Mazel D et al., EMBO J. 13(4):914-23 (1994)). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that will inhibit PDF are attractive candidates for development of new antimicrobial and antibacterial drugs. Prokaryotic organisms, including disease-causing prokaryotes, are described in Balows, A., H. G. Truper, M. Dworkin, W. Harder, and K. -H. Schleifer (eds.), The Prokaryotes, 2nd ed., New York: Springer-Verlag, 1992; and Holt, J. G. (editor-in-chief). Bergey""s Manual of Systematic Bacteriology, Vols. 1-4, Baltimore: Williams and Wilkins, 1982, 1986, 1989.
PDF is part of the metalloproteinase superfamily. While PDF clearly shares many of the features which characterize metalloproteinases, it differs from other members of the superfamily in several important respects. First, the metal ion in the active enzyme appears to be Fe (II), or possibly another divalent cationic metal, instead of the zinc ion more commonly encountered. Rajagopalan et al., J. Am. Chem. Soc., 119:12418-19 (1997). Second, the divalent ion appears to play an important role, not only in catalysis, but also in the structural integrity of the protein. Third, the third ligand of the divalent ion is a cysteine, rather than a histidine or a glutamate, as in other metalloproteinases and is not located at the C-terminal side of the HEXXH motif but far away along the amino acid sequence and N-terminal to the motif. Finally, the solution structure shows significant differences in the secondary and tertiary structure of PDF compared to other prototypical metalloproteinases see Meinnel et al. J. Mol. Biol. 262:375-386 (1996). PDF from E. coli, Bacillus stearothermophilus, and Thermus thermophilus have been characterized see Meinnel et al., J. Mol. Biol. 267:749-761 (1997). The enzyme studied by Meinnel et al. contained a zinc ion as the divalent ion and the structural features summarized above were obtained from zinc-containing proteins. The structure of the protein has also been determined by NMR (see O""Connell et al., J. Biomol. NMR 13(4):311-24 (1999)).
Metalloproteinases are critical to many aspects of normal metabolism. The class known as matrix metalloproteinases (MMPs) are involved in tissue remodeling, such as degradation of the extracellular matrix. These enzymes are believed to play a role in normal or beneficial biological events such as the formation of the corpus luteum during pregnancy (see Liu et al., Endocrinology 140(11):5330-8 (1999)), wound healing (Yamagiwa et al., Bone 25(2):197-203 (1999)), and bone growth in healthy children (Bord et al., Bone 23(1):7-12 (1998)). Disorders involving metalloproteinases have been implicated in several diseases such as cancer, arthritis, and autoimmune diseases.
Because of the importance of MMPs in normal physiological processes, it would be preferable to develop agents that inhibit PDF, a metalloproteinase present only in prokaryotes, while avoiding significant inhibition of MMPs. Alternatively, PDF inhibitors which also inhibit MMPs can be of use where the therapeutic benefits of inhibiting PDF outweigh the risk of side effects from MMP inhibition.
A wide variety of compounds have been developed as candidate inhibitors of MMPs and other metalloproteinases, and much effort has also been directed at synthetic methods for these compounds and related compounds. See Izquierdo-Martin et al. (1992) J. Sm. Chem. Soc. 114:325-331; Cushman et al. (1981) Chapter 5 xe2x80x9cSpecific Inhibitors of Zinc Metallopeptidasesxe2x80x9d in Topics in Molecular Pharmacology (Burgen and Roberts, eds.); Mohler et al. Nature 370:218-220 (1994); Gearing et al., Nature 370:555-557 (1994); McGeehan et al., Nature 370:558-561 (1994); U.S. Pat. Nos. 4,052,511, 4,303,662, 4,311,705, 4,321,383, 4,599,361, 4,804,676, 5,128,346, 5,256,657, 5,268,384, 5,447,929, 5,453,423, 5,552,419, 5,614,625, 5,643,908, 5,712,300, and 5,869,518; European patent publications EP 236872, EP 274453, EP 334244, EP 423943, EP 489577, EP 489579, EP 497192, EP 574758; and International PCT Patent Applications Publication Nos. WO 90/05716, WO 90/05719, WO 91/02716, WO 92/13831, WO 92/22523, WO 93/09090, WO 93/09097, WO 93/20047, WO 93/24449, WO 93/24475, WO 94/02446, WO 94/02447, WO 94/21612, WO 94/25434, WO 94/25435, WO 95/33731, WO 96/25156, WO 96/26918 WO 97/30707, WO 97/49674, WO 98/55449, and WO 99/02510.
Research on inhibitors of PDF is much less extensive than that for inhibitors of MMPs. N-formyl hydroxylamine derivatives are described in International Patent Application WO 99/39704. Peptide aldehyde inhibitors of PDFs are described in Durand et al., Arch. Biochem. Biophys., 367(2):297-302 (1999). The PDF inhibitor (S)-2-O-(H-phosphonoxy)-L-caproyl-L-leucyl-p-nitroanilide is described in Hao et al., Biochemistry 38:4712-4719 (1999), and peptidyl H-phosphonate inhibitors of PDF are discussed in Hu et al., Bioorg. Med. Chem. Lett. 8:2479-2482 (1998). Formylated peptides and pseudopeptides are described in Meinnel et al., Biochemistry 38(14):4288-4295 (1999) as inhibitors of PDF.
In view of the importance of identifying new antibiotics to treat bacteria resistant to existing antibiotics, and the relatively small amount of work that has been carried out on PDF inhibitors, it is desirable to develop novel inhibitors of PDF for evaluation and use as antibacterial and antimicrobial agents. The present invention fulfills this need.
In one aspect, this invention is directed to a compound of Formula (I): 
wherein:
R1 is hydrogen, halo, xe2x80x94OH, xe2x80x94R8OR9, xe2x80x94R9, xe2x80x94OR9, xe2x80x94SH, xe2x80x94SR9, xe2x80x94NH2, xe2x80x94NHR9 xe2x80x94NR9R10, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR9C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R9, xe2x80x94NR9C(xe2x95x90O)R10, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR9C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR9, xe2x80x94NHC(xe2x95x90O)NR9R10, xe2x80x94NR9C(xe2x95x90O)NR9aR10, xe2x80x94NHC(xe2x95x90O)OR9, xe2x80x94NR9C(xe2x95x90O)OR10, xe2x80x94NHS(xe2x95x90O)2R9, xe2x80x94NR9S(xe2x95x90O)2R10, xe2x80x94NHS(xe2x95x90O)2OR9, or xe2x80x94NR9S(xe2x95x90O)2OR10 where R8 is selected from the group consisting of xe2x80x94C1-C12 alkylene, substituted alkylene, or heteroalkylene, xe2x80x94C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, xe2x80x94C1-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and xe2x80x94(C1-C8 alkylene or substituted alkylene)n1xe2x80x94(C3-C12 arylene or heteroarylene)(C1-C8 alkyl or substituted alkyl)n2 where n1 and n2 are independently 0 or 1; and R9, R9a and R10 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n3xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n4 where n3 and n4 are independently 0 or 1;
R2 is independently hydrogen or xe2x80x94R9 wherein R9 is as defined above;
R3 is hydrogen, halo, xe2x80x94R11, xe2x80x94OH, xe2x80x94OR11, xe2x80x94R12OR11, xe2x80x94SH, xe2x80x94SR11, xe2x80x94NH2, xe2x80x94NHR11, xe2x80x94NR11R13, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR11C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11C(xe2x95x90O)R13, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR11C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR11, xe2x80x94NHC(xe2x95x90O)NR11R13, xe2x80x94NR11C(xe2x95x90O)NR11aR13, xe2x80x94NHC(xe2x95x90O)OR11, xe2x80x94NR11C(xe2x95x90O)OR13, xe2x80x94NHS(xe2x95x90O)2R13, xe2x80x94NR11S(xe2x95x90O)2R13, xe2x80x94NHS(xe2x95x90O)2OR11, or xe2x80x94NR11S(xe2x95x90O)2OR13, where R12 is selected from the group consisting of xe2x80x94C1-C12 alkylene, substituted alkylene, or heteroalkylene, xe2x80x94C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, xe2x80x94C1-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and xe2x80x94(C1-C8 alkylene or substituted alkylene)n5xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and R11, R11a and R13 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R4 is hydrogen or xe2x80x94R11 where xe2x80x94R11 is as defined above;
n is an integer from 1 to 5;
zero or one Y is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR11xe2x80x94 where R11 is as defined above, and xe2x80x94Sxe2x80x94, and all remaining Y are xe2x80x94CR6R7xe2x80x94 where R6 and R7 are each independently selected from the group consisting of hydrogen, xe2x80x94R14, xe2x80x94OH, xe2x80x94OR14, xe2x80x94SH, xe2x80x94SR14, xe2x80x94NH2, xe2x80x94NHR14, xe2x80x94NR14R15, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)R14, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NHR14, xe2x80x94C(xe2x95x90O)NR14R15, xe2x80x94C(xe2x95x90O)OH, xe2x80x94C(xe2x95x90O)OR14, xe2x80x94C(xe2x95x90O)SH, xe2x80x94C(xe2x95x90O)SR14, xe2x80x94C(xe2x95x90O)CH3, xe2x80x94C(xe2x95x90O)CH2R14, xe2x80x94C(xe2x95x90O)CHR14R15, xe2x80x94(xe2x95x90O)CR14R15R16, xe2x80x94(xe2x95x90O)OCH3, xe2x80x94(xe2x95x90O)OCH2R14, xe2x80x94(xe2x95x90O)OCHR14R15, xe2x80x94(xe2x95x90O)OCR14R15R16, xe2x80x94S(xe2x95x90O)2NH2, xe2x80x94S(xe2x95x90O)2NHR14, xe2x80x94S(xe2x95x90O)2NR14R15, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94N(R14)C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R15, xe2x80x94N(R14)C(xe2x95x90O)R15, xe2x80x94NHC(xe2x95x90O)OR14, xe2x80x94NHS(xe2x95x90O)2H, xe2x80x94N(R14)S(xe2x95x90O)2H, xe2x80x94NHS(xe2x95x90O)2OR15, xe2x80x94N(R14)S(xe2x95x90O)2OR5, xe2x80x94N(H)S(xe2x95x90O)2R15, xe2x80x94N(R14)S(xe2x95x90O)2R15 and where two vicinal R6 or R7 groups combine to form a substituted or unsubstituted xe2x80x94C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group where R14, R15 and R16 are each independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or when R14 and R15 are attached to a nitrogen atom they can combine to form a substituted or unsubstituted xe2x80x94C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
Preferably the compound of Formula (I) inhibits peptidyl deformylase at an IC50 of less than or equal to about 100 nm, preferably of less than or equal to 10 nm, more preferably of less than or equal to 1 nm.
Preferably the compound of Formula (I) displays a selectivity for peptidyl deformylase over at least one metalloproteinase selected from the group consisting of ACE and Matrilysin of greater than or equal to about 10 times, more preferably of greater than or equal to about 100 times, still more preferably of greater than or equal to about 1000 times.
In a second aspect, this invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method of treatment of a disease in a mammal treatable by administration of a peptidyl deformylase inhibitor which method comprises administration of a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient either alone or in combination with other pharmacologically active agents. In particular, the compounds of this invention are useful in treating microbial diseases. The microbial infection can be due to bacteria, other prokaryotes, or other organisms, including parasites, dependent on peptide deformylase for growth or survival.
In a fourth aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salts thereof in the preparation of a medicament for use in the treatment of diseases mediated by peptidyl deformylase enzyme.
In a fifth aspect, this invention is directed to a method for identifying compounds useful in treating microbial infections, comprising performing an assay to identify compounds which meet the criterion of either i) an IC50 for peptide deformylase of less than or equal to about 1 xcexcM, or ii) an MIC for a disease-causing pathogen of less than or equal to about 32 xcexcg/ml; performing an assay to identify compounds which meet the criterion of iii) displaying a selectivity for peptide deformylase over at least one metalloproteinase selected from the group consisting of Angiotensin Converting Enzyme (ACE) and Matrilysin of greater than or equal to about 10 times; and selecting compounds which meet either both criteria i) and iii), or both criteria ii) and iii). More preferably, the compounds so identified meet the criterion of either i) an IC50 for peptide deformylase of less than or equal to about 100 nM, or ii) an MIC for a disease-causing pathogen of less than or equal to about 10 xcexcg/ml.
Unless otherwise stated, the following terms as used in the specification have the following meaning.
The term xe2x80x9calkylxe2x80x9d refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms. Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, and adamantyl. Cyclic alkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbomyl.
The term xe2x80x9calkylenexe2x80x9d means a saturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl-propylene, butylene, pentylene, cyclopentylmethylene, and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d means an alkyl group as defined above that is substituted with one or more substituents, preferably one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. The phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but are not limited to, xe2x80x94CF3, xe2x80x94CF2xe2x80x94CF3, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2-carboxyethyl, methoxycarbonylmethyl, 1- or 2-methoxycarbonyl ethyl, benzyl, and the like.
The term xe2x80x9csubstituted alkylenexe2x80x9d means an alkylene group as defined above that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. The phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide. Examples of substituted alkyl groups include, but are not limited to, xe2x80x94CF2xe2x80x94, xe2x80x94CF2xe2x80x94CF2xe2x80x94, hydroxymethylene, 1- or 2-hydroxyethylene, methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxyethylene, and the like.
The term xe2x80x9calkenylxe2x80x9d refers to unsaturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one double bond (xe2x80x94Cxe2x95x90Cxe2x80x94). Examples of alkenyl groups include, but are not limited to, allyl vinyl, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2-cyclopentenyl and xe2x80x94CH2xe2x80x94CH2-cyclohexenyl where the ethyl group can be attached to the cyclopentenyl, cyclohexenyl moiety at any available carbon valence.
The term xe2x80x9calkenylenexe2x80x9d refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one double bond (xe2x80x94Cxe2x95x90Cxe2x80x94). Examples of alkenylene groups include, but are not limited to, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(cyclopentenyl)xe2x80x94 and the like.
The term xe2x80x9calkynylxe2x80x9d refers to unsaturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond (xe2x80x94Cxe2x89xa1Cxe2x80x94). Examples of alkynyl groups include, but are not limited to, acetylene, 2-butynyl, and the like.
The term xe2x80x9calkynylenexe2x80x9d refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond (xe2x80x94Cxe2x89xa1Cxe2x80x94). Examples of alkynylene groups include, but are not limited to, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, and the like.
The term xe2x80x9csubstituted alkenylxe2x80x9d or xe2x80x9csubstituted alkynyl,xe2x80x9d refers to the alkenyl and alkynyl groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of substituted alkenyl and alkynyl groups include, but are not limited to, xe2x80x94CHxe2x95x90CF2, hydroxyethenyl, methoxypropenyl, hydroxypropynyl, and the like.
The term xe2x80x9csubstituted alkenylenexe2x80x9d or xe2x80x9csubstituted alkynylene,xe2x80x9d refers to the alkenylene and alkynylene groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
The term xe2x80x9carylxe2x80x9d or xe2x80x9cArxe2x80x9d refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (including, but not limited to, groups such as phenyl) or multiple condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups. Substituted aryl is an aryl group that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
Representative examples include, but are not limited to, naphthyl, phenyl, chlorophenyl, iodophenyl, methoxyphenyl, carboxyphenyl, and the like.
The term xe2x80x9carylenexe2x80x9d refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9cthioalkoxyxe2x80x9d means a radical xe2x80x94SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
The term xe2x80x9cmono and xe2x80x9cdialkylaminoxe2x80x9d means a radical xe2x80x94NHR and xe2x80x94NRRxe2x80x2 respectively where R and Rxe2x80x2 independently represent an alkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)-amino, (cyclohexylmethyl)(ethyl)amino, and the like.
The term xe2x80x9cacyloxyxe2x80x9d means a radical xe2x80x94OC(O)R, where R is hydrogen, alkyl, aryl, heteroaryl or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein. Representative examples include, but are not limited to formyl, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy, benzoyloxy, benzylcarbonyloxy, and the like.
The term xe2x80x9cheteroalkyl,xe2x80x9d xe2x80x9cheteroalkenyl,xe2x80x9d and xe2x80x9cheteroalkynylxe2x80x9d refers to alkyl, alkenyl, and alkynyl groups respectively as defined above, that contain the number of carbon atoms specified (or if no number is specified, having 1 to 12 carbon atoms) which contain one or more heteroatoms, preferably one to three heteroatoms, as part of the main, branched, or cyclic chains in the group. Heteroatoms are independently selected from the group consisting of xe2x80x94NRxe2x80x94, xe2x80x94NRR, (where each R is hydrogen or alkyl), xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SR (R is hydrogen or alkyl), xe2x80x94OR (R is hydrogen or alkyl), and P; preferably xe2x80x94NR where R is hydrogen or alkyl and/or O. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups such as xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94Sxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH3, 1-ethyl-6-propylpiperidino, 2-ethylthiophenyl, piperazino, pyrrolidino, piperidino, morpholino, and the like. Examples of heteroalkenyl groups include, but are not limited to, groups such as xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94CH(CH3)xe2x80x94CH3, and the like.
The term xe2x80x9ccarboxaldehydexe2x80x9d means xe2x80x94CHO.
The term xe2x80x9ccarboalkoxyxe2x80x9d means xe2x80x94C(O)OR where R is alkyl as defined above and include groups such as methoxycarbonyl, ethoxycarbonyl, and the like.
The term xe2x80x9ccarboxamidexe2x80x9d means xe2x80x94C(O)NHR or C(O)NRRxe2x80x2 where R and Rxe2x80x2 are independently hydrogen or alkyl as defined above. Representative examples include groups such as aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d or xe2x80x9cHetArxe2x80x9d refers to an aromatic carbocyclic group of 3 to 9 ring atoms forming a single ring and having at least one hetero atom, preferably one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring. Representative examples include, but are not limited to single ring such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyridyl, thiophene, and the like, or multiple condensed rings such as indolyl, quinoline, quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.
The heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be unsubstituted or substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of such substituted heteroalkyl groups include, but are not limited to, piperazine, pyrrolidine, morpholine, or piperidine, substituted at a nitrogen or carbon by a phenyl or benzyl group, and attached to the remainder of the molecule by any available valence on a carbon or nitrogen, xe2x80x94NHxe2x80x94SO2-phenyl, xe2x80x94NHxe2x80x94(Cxe2x95x90O)O-alkyl, xe2x80x94NHxe2x80x94(Cxe2x95x90O)O-alkyl-aryl, and the like. The heteroatom(s) as well as the carbon atoms of the group can be substituted. The heteroatom(s) can also be in oxidized form.
The term xe2x80x9cheteroarylenexe2x80x9d refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridinylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like.
The term xe2x80x9cheteroalkylenexe2x80x9d, xe2x80x9cheteroalkenylenexe2x80x9d, and xe2x80x9cheteroalkynylenexe2x80x9d refers to the diradical group derived from heteroalkyl, heteroalkenyl, and heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and heteroalkynyl), as defined above.
The term xe2x80x9calkylarylxe2x80x9d refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl, alkenyl, or alkynyl linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, tert-butoxy, and allyloxy.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to an aryl group linked to an oxygen atom at one of the ring carbons. Examples of alkoxy groups include, but are not limited to, groups such as phenoxy, 2-, 3-, or 4-methylphenoxy, and the like.
The term xe2x80x9chalogenxe2x80x9d as used herein refer to Cl, Br, F or I substituents, preferably fluoro or chloro.
The term xe2x80x9cxe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkylxe2x80x9d means an alkyl, substituted alkyl or heteroalkyl group respectively as defined above and having 1 to 12 carbon atoms. For example, when R1 is xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl it means that R1 can be xe2x80x94(C1-C12) alkyl or xe2x80x94(C1-C12)substituted alkyl, or xe2x80x94(C1-C12)heteroalkyl.
The term xe2x80x9cxe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenylxe2x80x9d means an alkenyl, substituted alkenyl, or heteroalkenyl group as defined above and having 1 to 12 carbon atoms.
The xe2x80x9cxe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynylxe2x80x9d means an alkynyl, substituted alkynyl, or heteroalkynyl group as defined above and having 1 to 12 carbon atoms.
The term xe2x80x9cxe2x80x94(C1-C12) alkylene, substituted alkylene, or heteroalkylenexe2x80x9d means an alkylene, substituted alkylene, or heteroalkylene group as defined above and having1 to 12 carbon atoms.
The term xe2x80x9cxe2x80x94(C1-C12) alkenylene, substituted alkenylene, or heteroalkenylenexe2x80x9d means that the alkenylene, substituted alkenylene, or heteroalkenylene group as defined above and having 1 to 12 carbon atoms.
The term xe2x80x9cxe2x80x94(C1-C12) alkynylene, substituted alkynylene, or heteroalkynylenexe2x80x9d means an alkynylene, substituted alkynylene, or heteroalkynylene group as defined above and having 1 to 12 carbon atoms.
The term xe2x80x9cand xe2x80x94(C1-C8 alkylene or substituted alkylene)n5xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1xe2x80x9d means that xe2x80x9cwhen n5 and/or n6 are 0 then xe2x80x94(C1-C8 alkylene or substituted alkylene)n5 and/or xe2x80x94(C1-C8 alkylene or substituted alkylene)n6xe2x80x9d are a covalent bond or when n5 and/or n6 are 1, then the alkylene or substituted alkylene group is present and can have 1 to 8 carbon atoms. The term xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94means that the arylene has 6 to 12 carbon atoms (e.g., phenylene, naphtylene, and the like) and heteroarylene groups have 3 to 12 carbons atoms and additionally contain one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring (e.g., 2,6-pyridylene, 2,4-pyridinylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridylene, 2,5-indolenyl, and the like) in accordance with the definition of the heteroarylene above. Additionally, it will be recognized by a person skilled in the art that when xe2x80x9cxe2x80x94(C1-C8 alkylene or substituted alkylene)xe2x80x94xe2x80x9d and xe2x80x9cxe2x80x94(C1-C8 alkyl or substituted alkyl)xe2x80x94xe2x80x9d are a covalent bond then xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94 is an aryl or heteroaryl group as defined above.
xe2x80x9cProtecting groupxe2x80x9d refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley and Sons, Inc., New York). Preferred amino protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBDIMS), 9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like. Preferred hydroxyl protecting groups include Fmoc, TBDIMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether). Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy-methyloxycarbonyl).
xe2x80x9cInhibitorxe2x80x9d refers to a compound that interferes with the interaction between a target and its respective substrate(s) or endogenous ligand(s). Target molecules include, but are not limited to, enzymes and receptors. Enzyme inhibitors have been extensively studied from kinetic and mechanistic standpoints; see, e.g., Fersht, A., Enzyme Structure and Mechanism, 2nd Ed., New York, W. H. Freeman, 1985. A useful measure of the effectiveness of a compound at inhibiting enzyme catalysis is the IC50 of that compound. The IC50 of a compound can determined by the equation
y=yo/(1+[In]/IC50)
where y is the measured reaction velocity, yo is the reaction velocity in the absence of inhibitor, and [In] is the inhibitor concentration. Solving this equation at the inhibitor concentration [In] when y=yo/2 yields IC50 of the inhibitor for the enzyme under study. Useful inhibitors have an IC50 equal to or less than about 10 TM, preferably equal to or less than about 1 TM. More preferably, the inhibitor has an IC50 equal to or less than about 100 nM, still more preferably equal to or less than about 10 nM, even more preferably equal to or less than about 1 nM. Most preferably, inhibitors have an IC50 equal to or less than about 100 pM, or equal to or less than about 10 pM.
A selective inhibitor refers to an inhibitor that will inhibit the activity of one macromolecule, typically an enzyme, while exhibiting little or no inhibitory effect on another macromolecule, typically another enzyme. The compounds of the invention are particularly useful in that they display selective inhibition of peptidyl deformylase while exhibiting much lower inhibitory activity towards metalloproteinases such as matrilysin. The selectivity of an enzyme inhibitor can be indicated by dividing the IC50 of the compound for the enzyme which is not intended to be inhibited, by the IC50 of the compound for the enzyme which is intended to be inhibited. Thus, if a compound has an IC50 for matrilysin of 1 xcexcM, and an IC50 for peptidyl deformylase of 0.01 xcexcM, the compound displays a 100-fold (or 100 times) selectivity for peptidyl deformylase over matrilysin, or alternatively is said to be 100 times more selective for peptidyl deformylase compared to matrilysin. Useful compounds display a selectivity of greater than or equal to about 10 times, preferably greater than or equal to about 100 times, more preferably greater than or equal to about 1000 times, still more preferably greater than or equal to about 10,000, for peptidyl deformylase over one or more other metalloproteinases, for example for peptidyl deformylase over matrilysin.
The compounds of the invention are intended for use in eukaryotic animals. Preferably, the animal is a vertebrate; more preferably, the animal is a mammal; most preferably, the animal is a human.
By xe2x80x9chydroxamic acid derivative,xe2x80x9d xe2x80x9chydroxamic acid derivative compound,xe2x80x9d xe2x80x9chydroxamic acid compound,xe2x80x9d xe2x80x9chydroxamate derivative,xe2x80x9d xe2x80x9chydroxamate derivative compound,xe2x80x9d or xe2x80x9chydroxamate compoundxe2x80x9d is meant any compound containing the functional group HN(OH)xe2x80x94C(xe2x95x90O)xe2x80x94.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-superimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R6 substituent in a compound of Formula (I) is 2-hydroxyethyl, then the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
A compound of Formula (I) may act as a pro-drug. Prodrug means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred. For example,
(A) (i) A preferred group of compounds is that wherein R1 is hydrogen or hydroxy, preferably hydroxy. The stereochemistry at the carbon carrying the R1 group is (R) or (S).
(ii) Another preferred group of compounds is that wherein R1 is halo; preferably chloro or fluoro; more preferably fluoro. The stereochemistry at the carbon carrying the R1 group is (R) or (S), preferably (S) when R1 is fluoro.
Within the above preferred groups, a more preferred group of compounds is that wherein R2 and R4 are hydrogen.
(iii) Yet another preferred group of compounds is that wherein R3 is hydrogen or R11 where R11 is xe2x80x94C1-C12 alkyl or xe2x80x94(C1-C8 alkylene)n7xe2x80x94(C3-C12 aryl or heteroaryl), preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R). 
(iv) Yet another preferred group of compounds is that wherein the group is a group of formula: 
xe2x80x83wherein:
n is 1 or 2, preferably 1; and
R7is:
(a) xe2x80x94C(xe2x95x90O)NR14R15 where R14 and R15 are independently selected from the group consisting of hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or R14 and R15 combine to form a substituted or unsubstituted xe2x80x94(C4-C10)cyclc alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
Preferably, R7 is xe2x80x94C(xe2x95x90O)NR14R15 where R14 and R15 are each independently hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, heteroaryl or R14 and R15, when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group.
More preferably, R7 is xe2x80x94C(xe2x95x90O)NHR15 where R15 is H Or xe2x80x94(C1-C12) alkyl, aryl, or heteroaryl or xe2x80x94C(xe2x95x90O)NR14R15 and R14 where R15 form a substituted or unsubstituted xe2x80x94(C4-C10)cyclic heteroalkyl.
Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenyl-aminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutyl-aminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-yl-aminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methyltbiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-ylmethylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1-ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-yl-aminocarbonyl, 3,4-difluorophenyl-aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylaminocarbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, piperazin-1-yl-carbonyl, piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, homopiperdin-1-ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R7 is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2-ylaminocarbonyl.
More particularly, R7 is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) R7 is xe2x80x94NHC(xe2x95x90O)OR14 where R14 is hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1.
Preferably, R7 is xe2x80x94NHC(xe2x95x90O)OR14 where R14 is hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, heteroaryl; or
(c) R7 is xe2x80x94C(xe2x95x90O)OR14 where R14 is hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n 10 are independently 0 or 1.
Preferably, R7 is xe2x80x94C(xe2x95x90O)OR17 where R14 is hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, or heteroaryl.
More preferably, xe2x80x94C(xe2x95x90O)OR14 where R14 is alkyl, even more preferably R7 is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
The above defined embodiments of (i)-(iv) are employed either singularly or in any combination.
(B) Another preferred group of compounds is represented as Formula (IIa): 
xe2x80x83wherein:
R1 is xe2x80x94OH, xe2x80x94OR9, xe2x80x94R8OR9, xe2x80x94SH, xe2x80x94SR9, xe2x80x94NH2, xe2x80x94NHR9 xe2x80x94NR9R10, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR9C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R9, xe2x80x94NR9C(xe2x95x90O)R10, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR9C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR9, xe2x80x94NHC(xe2x95x90O)NR9R10, NR9C(xe2x95x90O)NR9aR10, xe2x80x94NHC(xe2x95x90O)OR9, xe2x80x94NR9C(xe2x95x90O)OR10, xe2x80x94NHS(xe2x95x90O)2R9, xe2x80x94NR9S(xe2x95x90O)2R10, xe2x80x94NHS(xe2x95x90O)2OR9, or xe2x80x94NR9S(xe2x95x90O)2OR10 where R9 is selected from the group consisting of xe2x80x94C1-C12 alkylene, xe2x80x94C1-C12 alkenylene, and xe2x80x94C1-C12 alkynylene and R9, R9a and R10 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, xe2x80x94C1-C12 alkenyl, and xe2x80x94C1-C12 alkynyl;
R2 is hydrogen or xe2x80x94R9 where R9 is as defined above;
R3 is xe2x80x94R11, xe2x80x94OH, xe2x80x94OR11, xe2x80x94R12OR11, xe2x80x94SH, xe2x80x94SR11, xe2x80x94NH2, xe2x80x94NHR11 xe2x80x94NR11R13, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR11C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11C(xe2x95x90O)R13, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR11C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR11, xe2x80x94NHC(xe2x95x90O)NR11R13, xe2x80x94NR11C(xe2x95x90O)NR11aR13, xe2x80x94NHC(xe2x95x90O)OR11, xe2x80x94NR11C(xe2x95x90O)OR13, xe2x80x94NHS(xe2x95x90O)2R13, xe2x80x94NR11S(xe2x95x90O)2R13, xe2x80x94NHS(xe2x95x90O)2OR11, or xe2x80x94NR11S(xe2x95x90O)2OR13, where R12 is selected from the group consisting of xe2x80x94C1-C12 alkylene, substituted alkylene, or heteroalkylene, xe2x80x94C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, xe2x80x94C1-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and xe2x80x94(C1-C8 alkylene or substituted alkylene)n5xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and R11, R11a, and R13 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R4is hydrogen or R11 where R11 is as defined above;
n is an integer from 1 to 5;
zero or one Y is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR11xe2x80x94 where R11 is as defined above, and xe2x80x94Sxe2x80x94, and all remaining Y are xe2x80x94CR6R7xe2x80x94 where R6 and R7 are each independently selected from the group consisting of hydrogen, xe2x80x94R14, xe2x80x94OH, xe2x80x94OR14, xe2x80x94SH, xe2x80x94SR14, xe2x80x94NH2, xe2x80x94NHR14, xe2x80x94NR14R15, xe2x80x94(xe2x95x90O)H, xe2x80x94(xe2x95x90O)R14, xe2x80x94(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NHR14, xe2x80x94C(xe2x95x90O)NR14R15, xe2x80x94C(xe2x95x90O)OH, xe2x80x94C(xe2x95x90O)OR14, xe2x80x94C(xe2x95x90O)SH, xe2x80x94C(xe2x95x90O)SR14, xe2x80x94C(xe2x95x90O)CH3, xe2x80x94C(xe2x95x90O)CH2R14, xe2x80x94C(xe2x95x90O)CHR14R15, xe2x80x94C(xe2x95x90O)CR14R15R16, xe2x80x94C(xe2x95x90O)OCH3, xe2x80x94C(xe2x95x90O)OCH2R14, xe2x80x94C(xe2x95x90O)OCHR14R15, xe2x80x94C(xe2x95x90O)OCR14R15R16, xe2x80x94S(xe2x95x90O)2NH2, xe2x80x94S(xe2x95x90O)2NHR14, xe2x80x94S(xe2x95x90O)2NR14R5, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94N(R14)C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R15, xe2x80x94N(R14)C(xe2x95x90O)R15, xe2x80x94NHS(xe2x95x90O)2H, xe2x80x94N(R14)S(xe2x95x90O)2H, xe2x80x94NHS(xe2x95x90O)2OR15, xe2x80x94N(R14)S(xe2x95x90O)2OR15, xe2x80x94N(H)S(xe2x95x90O)2R15, xe2x80x94N(R14)S(xe2x95x90O)2R15 and where two vicinal R6 or R7 groups combine to form a substituted or unsubstituted C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; where R14, R15 and R16 are each independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or a pharmaceutically acceptable salt thereof.
Within this group of compounds (IIa), a preferred group of compounds is that wherein the embodiments of (i)-(iv) defined below are employed either singularly or in any combination:
(i) A preferred group of compounds is that wherein R1 is hydrogen or hydroxy and the stereochemistry at the carbon carrying the R1 group is (R) or (S), preferably (S).
(ii) Another preferred group of compounds is that wherein R2 and R4 are hydrogen.
(iii) Another preferred group of compounds is that wherein R3 is hydrogen or R9 where R9 is xe2x80x94C1-C12 alkyl or xe2x80x94(C1-C8 alkylene)n7xe2x80x94(C3-C12 aryl or heteroaryl) where n7, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R).
(iv) Another preferred group of compounds is that wherein the 
xe2x80x83group is a group of formula: 
xe2x80x83wherein:
n is 1 or 2, preferably 1; and
R7 is:
(a) xe2x80x94C(xe2x95x90O)NR14R15 where R14 and R15 are independently selected from the group consisting of hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1.
Preferably, R7 is xe2x80x94C(xe2x95x90O)NR14R15 where R14 and R15 are each independently hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, heteroaryl. More preferably, R7 is xe2x80x94C(xe2x95x90O)NHR15 where R15 is H or xe2x80x94(C1-C12) alkyl, aryl, or heteroaryl.
Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenylaminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylamino-arbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutylaminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 3-methylbutylaminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-ylaminocarbonyl, 2,4-dimethoxyphenylaminocarbonyl, 3,4-methylenedioxyphen-5-ylmethylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1-ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenylaminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylaminocarbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R7 is ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2-ylaminocarbonyl. More particularly, R7 is phenylaminocarbonyl or pyrimidin-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) xe2x80x94NHC(xe2x95x90O)OR14 where R14 is hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. Preferably, R7 is xe2x80x94NHC(xe2x95x90O)OR14 where R14 is hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, heteroaryl; or
(c) xe2x80x94C(xe2x95x90O)OR14 where R14 is hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. Preferably, R7 is xe2x80x94C(xe2x95x90O)OR14 where R14 is hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, or heteroaryl. More preferably, xe2x80x94C(xe2x95x90O)OR14 where R14 is alkyl, even more preferably R7 is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
(C) Another preferred group of compounds is represented by Formula (IIb): 
xe2x80x83wherein:
R1 is xe2x80x94R9, xe2x80x94OH, xe2x80x94OR9, xe2x80x94R8OR9, xe2x80x94SH, xe2x80x94SR9, xe2x80x94NH2, xe2x80x94NHR9 xe2x80x94NR9R10, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR9C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R9, xe2x80x94NR9C(xe2x95x90O)R10, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR9C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR9, xe2x80x94NHC(xe2x95x90O)NR9R10, xe2x80x94NR9C(xe2x95x90O)NR9aR10, xe2x80x94NHC(xe2x95x90O)OR9, xe2x80x94NR9C(xe2x95x90O)OR10, xe2x80x94NHS(xe2x95x90O)2R9, xe2x80x94NR9S(xe2x95x90O)2R10, xe2x80x94NHS(xe2x95x90O)2OR9, or xe2x80x94NR9S(xe2x95x90O)2OR10 where R8 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n1xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n2 where n1 and n2 are independently 0 or 1; and R9, R9a, and R10 are each independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n3xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n4 where n3 and n4 are independently 0 or 1;
R2 is xe2x80x94H or xe2x80x94R9 where R9 is as defined above;
R3 is xe2x80x94R11, xe2x80x94OH, xe2x80x94OR11, xe2x80x94R12OR11, xe2x80x94SH, xe2x80x94SR11, xe2x80x94NH2, xe2x80x94NHR11, xe2x80x94NRaRb, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR11C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11C(xe2x95x90O)R13, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR11C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR11, xe2x80x94NHC(xe2x95x90O)NR11R13, xe2x80x94NR11C(xe2x95x90O)NR11aR13, xe2x80x94NHC(xe2x95x90O)OR11, xe2x80x94NR11C(xe2x95x90O)OR13, xe2x80x94NHS(xe2x95x90O)2R11, xe2x80x94NR11S(xe2x95x90O)2R13, xe2x80x94NHS(xe2x95x90O)2OR11, or xe2x80x94NR11S(xe2x95x90O)2OR13 where R12 is selected from the group consisting of xe2x80x94C1-C12 alkylene, substituted alkylene, or heteroalkylene, xe2x80x94C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, xe2x80x94C1-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and xe2x80x94(C1-C8 alkylene or substituted alkylene)n5xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and R11, R11a, and R13 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R4 is hydrogen or xe2x80x94R11 where R11 is as defined above;
R7 is xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)R14, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NHR14, xe2x80x94(xe2x95x90O)NR14R15, xe2x80x94C(xe2x95x90O)SH, or xe2x80x94C(xe2x95x90O)SR14 where where R14 and R15 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; and where R7 is xe2x80x94C(xe2x95x90O)NR14R15, then the R14 and R15 groups additionally can combine to form a substituted or unsubstituted C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
Within this group of compounds, a preferred group of compounds is that wherein the embodiments of (i)-(iv) defined below are employed either singularly or in any combination:
(i) A preferred group of compounds is that wherein R1 is hydroxy and the stereochemistry at the carbon carrying the R1 group is (R) or (S), preferably (S).
(ii) Another preferred group of compounds is that wherein R2 is hydrogen.
(iii) Another preferred group of compounds is that wherein R3 is hydrogen or R9 where R9 is xe2x80x94C1-C12 alkyl or xe2x80x94(C1-C8 alkylene)n5xe2x80x94(C3-C12 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R).
(iv) Yet another preferred group of compounds is that wherein R7 is:
(a) xe2x80x94C(xe2x95x90O)NHR14 where R14 is selected from the group consisting of xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. Preferably, R7 is xe2x80x94C(xe2x95x90O)NHR14 where R14 is xe2x80x94(C1-C12) alkyl, alkoxy, aryl, or heteroaryl. More preferably, R7 is xe2x80x94C(xe2x95x90O)NHR14where R14 is xe2x80x94(C1-C12) alkyl, aryl, or heteroaryl. Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenyl-aminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutylaminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-ylaminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-ylaminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-ylmethylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1-ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenylaminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylaminocarbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, homopiperdin-1-ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl. In particular, R7 is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2-ylaminocarbonyl.
More particularly, R7 is phenylaminocarbonyl or pyrimidin-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) R7 is xe2x80x94C(xe2x95x90O)OR14 where R14 is selected from the group consisting of hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. Preferably, R7 is xe2x80x94C(xe2x95x90O)OR14 where R17 is hydrogen, xe2x80x94(C1-C12) alkyl, alkoxy, aryl, or heteroaryl. More preferably, xe2x80x94C(xe2x95x90O)OR14 where R14 is alkyl, even more preferably R7 is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
(D) Another preferred group of compounds if represented by Formula (IIc): 
xe2x80x83wherein:
R1 is xe2x80x94OH, xe2x80x94OR9, xe2x80x94SH or xe2x80x94SR9 wherein R9 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n1xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n2 where n1 and n2 are independently 0 or 1;
R2 is hydrogen;
R3 is xe2x80x94R11, xe2x80x94OH, xe2x80x94OR11, xe2x80x94R12OR11, xe2x80x94SH, xe2x80x94SR11, xe2x80x94NH2, xe2x80x94NHR11, xe2x80x94NR11R13, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR11C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11C(xe2x95x90O)R13, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR11C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR11, xe2x80x94NHC(xe2x95x90O)NR11R13, xe2x80x94NR11C(xe2x95x90O)NR11aR13, xe2x80x94NHC(xe2x95x90O)OR11, xe2x80x94NR11C(xe2x95x90O)OR13, xe2x80x94NHS(xe2x95x90O)2R11, xe2x80x94NR11S(xe2x95x90O)2R13, xe2x80x94NHS(xe2x95x90O)2OR11, or xe2x80x94NR11S(xe2x95x90O)2OR13 where R12 is selected from the group consisting of xe2x80x94C1-C12 alkylene, substituted alkylene, or heteroalkylene, xe2x80x94C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, xe2x80x94C1-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and xe2x80x94(C1-C8 alkylene or substituted alkylene)n5xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl) n6 where n5 and n6 are independently 0 or 1; and R11 and R13 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R4 is hydrogen or xe2x80x94R11 wherein R11 is as defined above; and
R7 is xe2x80x94C(xe2x95x90O)OR14, where R14 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or
a pharmaceutically acceptable salt thereof.
In another embodiment of this series of compounds, R1 is xe2x80x94OH or xe2x80x94OR9. In another embodiment of this series of compounds, R3 is xe2x80x94C1-C12 alkyl, such as C4 alkyl and R4 is H. In another embodiment of this series of compounds, R14 is xe2x80x94C(xe2x95x90O)Oxe2x80x94C1-C12 alkyl, such as xe2x80x94C(xe2x95x90O)Oxe2x80x94C1-C4 alkyl, for example xe2x80x94C(xe2x95x90O)O-t-butyl.
(E) Another preferred group of compounds if represented by Formula (IId): 
xe2x80x83wherein:
R3 is xe2x80x94R11 where R11 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1; and
R7 is xe2x80x94C(xe2x95x90O)OR14 where R14 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or a pharmaceutically acceptable salt thereof.
In one embodiment, R3 is xe2x80x94(C1-C12)alkyl, preferably n-butyl. In another embodiment of this series of compounds, R7 is xe2x80x94C(O)Oxe2x80x94C1-C12 alkyl, such as xe2x80x94C(O)Oxe2x80x94C1-C4 alkyl, for example xe2x80x94C(O)O-tert-butyl.
(F) Another preferred group of compounds if represented by Formula (IIe): 
xe2x80x83wherein:
R3 is xe2x80x94R11 where xe2x80x94R11 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R7 is xe2x80x94NH2, xe2x80x94NHR13, or xe2x80x94NHR14R15 where R13, R14 and R15 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or where R14 and R15 combine to form a substituted or unsubstituted C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is C1-C12 alkyl, preferably n-butyl. In another embodiment of this series of compounds, R7 is xe2x80x94NHR13 where R13 is as defined above.
(G) Another preferred group of compounds if represented by Formula (IIf): 
xe2x80x83wherein:
R3 is xe2x80x94R11 wherein R11 is selected from the group consisting of hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R7a, R7b, R7cand R7d are independently selected from the group consisting of hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or two vicinal R7 groups can combine to form a substituted or unsubstituted C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is n-butyl. In another embodiment of this series of compounds, at least one R7 is selected from the group consisting of xe2x80x94C(xe2x95x90O)OR14, xe2x80x94OH, xe2x80x94OR14, xe2x80x94R14, xe2x80x94NH(Cxe2x95x90O)OR14, or xe2x80x94NH(Cxe2x95x90O)R15, where R14 and R15 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and (C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1.
(H) Another preferred group of compounds if represented by Formula (IIg): 
xe2x80x83wherein:
R3 is xe2x80x94R11 where R11 is selected from the group consisting of hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1; and
R7a is selected from the group consisting of hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or a pharmaceutically acceptable salt thereof.
In another embodiment of this series of compounds, R7a is xe2x80x94CH2xe2x80x94Rd where Rd is selected from the group consisting of H, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. In another embodiment of this series of compounds, Rd is selected from the group consisting of xe2x80x94Oxe2x80x94CH3, xe2x80x94OH, xe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94CH3, and 
(I) Another preferred group of compounds if represented by Formula (IIh): 
xe2x80x83wherein:
R3 is xe2x80x94R11 where R11 is selected from the group consisting of hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1; and
R7 is selected from the group consisting of xe2x80x94R14 or xe2x80x94OR14 where R14 is selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or
a pharmaceutically acceptable salt thereof.
In one embodiment of this series of compounds, R3 is n-butyl. In another embodiment of this series of compounds, R7 is xe2x80x94OCH3 or xe2x80x94O-tert-butyl.
(J) Another preferred group of compounds if represented by Formula (IIi): 
xe2x80x83wherein:
R3 is xe2x80x94R11 where R11 is hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1; and
R30a, R30b, R30c, R30d, and R30e are independently selected from the group consisting of hydrogen, xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or where two vicinal R30 groups can combine to form a substituted or unsubstituted C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; and all salts and stereoisomers thereof.
In one embodiment of this series of compounds, at least one R30 is selected from the group consisting of xe2x80x94(xe2x95x90O)OR15 and xe2x80x94(xe2x95x90O)R15, where R15 is independently selected from the group consisting of C1-C12 alkyl, substituted alkyl, or heteroalkyl, C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and (C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1.
(K) Another preferred group of compounds if represented by Formula (IIj): 
xe2x80x83where:
R1 is halo;
R3 is hydrogen, R11, xe2x80x94OH, xe2x80x94OR11, xe2x80x94R12OR11, xe2x80x94SH, xe2x80x94SR11, xe2x80x94NH2, xe2x80x94NHR11, xe2x80x94NR11R13, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94NR11C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11C(xe2x95x90O)R13, xe2x80x94NHC(xe2x95x90O)NH2, xe2x80x94NR11C(xe2x95x90O)NH2, xe2x80x94NHC(xe2x95x90O)NHR11, xe2x80x94NHC(xe2x95x90O)NR11R13, xe2x80x94NR11C(xe2x95x90O)NR11aR13, xe2x80x94NHC(xe2x95x90O)OR11, xe2x80x94NR11C(xe2x95x90O)OR13, xe2x80x94NHS(xe2x95x90O)2R13, xe2x80x94NR11S(xe2x95x90O)2R13, xe2x80x94NHS(xe2x95x90O)2OR11, or xe2x80x94NR11S(xe2x95x90O)2OR13, where R12 is selected from the group consisting of xe2x80x94C1-C12 alkylene, substituted alkylene, or heteroalkylene, xe2x80x94C1-C12 alkenylene, substituted alkenylene, or heteroalkenylene, xe2x80x94C1-C12 alkynylene, substituted alkynylene, or heteroalkynylene, and xe2x80x94(C1-C8 alkylene or substituted alkylene)n5xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n6 where n5 and n6 are independently 0 or 1; and R11, R11a and R13 are independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n7xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n8 where n7 and n8 are independently 0 or 1;
R7 is hydrogen, R14, xe2x80x94OH, xe2x80x94OR14, xe2x80x94SH, xe2x80x94SR14, xe2x80x94NH2, xe2x80x94NHR14, xe2x80x94NR14R15, xe2x80x94(xe2x95x90O)H, xe2x80x94(xe2x95x90O)R14, xe2x80x94(xe2x95x90O)NH2, xe2x80x94(xe2x95x90O)NHR14, xe2x80x94(xe2x95x90O)NR14R15, xe2x80x94(xe2x95x90O)OH, xe2x80x94(xe2x95x90O)OR14, xe2x80x94(xe2x95x90O) SH, xe2x80x94(xe2x95x90O)SR14, xe2x80x94(xe2x95x90O)CH3, xe2x80x94(xe2x95x90O)CH2R14, xe2x80x94(xe2x95x90O)CHR14R15, xe2x80x94(xe2x95x90O)CR14R15R16, xe2x80x94(xe2x95x90O)OCH3, xe2x80x94(xe2x95x90O)OCH2R14, xe2x80x94(xe2x95x90O)OCHR14R15, xe2x80x94(xe2x95x90O)OCR14R15R16, xe2x80x94S(xe2x95x90O)2NH2, xe2x80x94S(xe2x95x90O)2NHR14, xe2x80x94S(xe2x95x90O)2NR14R15, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94N(R14)C(xe2x95x90O)H, xe2x80x94NHC(xe2x95x90O)R15, xe2x80x94N(R14)C(xe2x95x90O)R15, xe2x80x94NHC(xe2x95x90O)OR14, xe2x80x94NHS(xe2x95x90O)2H, xe2x80x94N(R14)S(xe2x95x90O)2H, xe2x80x94NHS(xe2x95x90O)2OR15, xe2x80x94N(R14)S(xe2x95x90O)2OR15, xe2x80x94N(H)S(xe2x95x90O)2R15, or xe2x80x94N(R14)S(xe2x95x90O)2R15, or where two vicinal R6 or R7 groups combine to form a substituted or unsubstituted xe2x80x94C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group where R14, R15 and R16 are each independently selected from the group consisting of xe2x80x94C1-C12 alkyl, substituted alkyl, or heteroalkyl, xe2x80x94C1-C12 alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94C1-C12 alkynyl, substituted alkynyl, or heteroalkynyl, and xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)xe2x80x94(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or when R14 and R15 are attached to a nitrogen atom they can combine to form a substituted or unsubstituted C4-C10 cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
Within this group of compounds, a preferred group of compounds is that wherein the embodiments of (i)-(iii) defined below are employed either singularly or in any combination:
(i) A preferred group of compounds is that wherein R1 is fluoro. The stereochemistry at the carbon carrying the R1 group is (R) or (S), preferably (S).
(ii) Another preferred group of compounds is that wherein R3 is hydrogen or R9 where R9 is xe2x80x94C1-C12 alkyl or xe2x80x94(C1-C8 alkylene)n5xe2x80x94(C3-C12 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl. The stereochemistry at the carbon carrying the R3 group is (R) or (S), preferably (R); and
(iii) R7 is:
(a)xe2x80x94(xe2x95x90O)NR14R15, where R14 and R15 are independently hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1; or R14 and R15 combine to form a substituted or unsubstituted xe2x80x94(C4-C10)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group.
Preferably, R7 is xe2x80x94(xe2x95x90O)NR14R15 where R14 and R15 are each independently hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, heteroaryl or R14 and R15, when attached to the same carbon, combine to form a cyclic heteroalkyl, aryl or heteroaryl group. More preferably, R7 is xe2x80x94(xe2x95x90O)NHR15 where R15 is H or xe2x80x94(C1-C12) alkyl, aryl, or heteroaryl or xe2x80x94(xe2x95x90O)NR14R15 where R14 and R15form a substituted or unsubstituted xe2x80x94(C4-C10)cyclic heteroalkyl.
Even more preferably R7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylpropylaminocarbonyl, 2-(cyclohexen-1-yl)-ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, 4-tert-butylphenylaminocarbonyl, 4-tert-butylaminocarbonyl, indan-2-ylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl, 4-phenylthiazol-2-ylaminocarbonyl, 5-phenylthiadiazol-2-ylaminocarbonyl, 5-ethylthiadiazol-3-ylaminocarbonyl, thiadiazol-2-ylaminocarbonyl, 3-trifluoromethoxyphenylaminocarbonyl, 2,5-dimethylphenylaminocarbonyl, 2,5-dimethoxyphenylaminocarbonyl, 3,4-dichlorophenylaminocarbonyl, benzthiazol-2-ylaminocarbonyl, 3-phenoxyphenylaminocarbonyl, 2-hydroxybutylaminocarbonyl, 4-hydroxybutylaminocarbonyl, 1,4-benzodioxan-6-ylaminocarbonyl, isoquinolin-6-ylaminocarbonyl, methylaminocarbonyl, thiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 3-methylbutyl-aminocarbonyl, n-pentylaminocarbonyl, cyclohexylaminocarbonyl, 5-methylthiazol-2-ylaminocarbonyl, 4-methylthiazol-2-yl-aminocarbonyl, 2,4-dimethoxyphenyl-aminocarbonyl, 3,4-methylenedioxyphen-5-ylmethylaminocarbonyl, allylaminocarbonyl, 2-methylallylaminocarbonyl, pyrrolidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, indan-1-ylaminocarbonyl, 2-methoxyethylaminocarbonyl, indan-5-ylaminocarbonyl, 3,4-difluorophenyl-aminocarbonyl, 5-methylisoxazol-5-ylaminocarbonyl, 3-fluorophenylaminocarbonyl, 4-fluorophenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, 2-propylaminocarbonyl, 2-phenylpropylaminocarbonyl, n-propylaminocarbonyl, N-ethyl-N-(n-butyl)aminocarbonyl, benzylaminocarbonyl, thiazolidin-1-ylcarbonyl, piperazin-1-yl-carbonyl, piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, homopiperdin-1-ylcarbonyl, pyrimidin-2-ylaminocarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-methylpyrimidin-2-ylaminocarbonyl, pyrimidin-4-ylaminocarbonyl, pyrazin-2-ylaminocarbonyl, imidazol-2-ylaminocarbonyl.
In particular, R7 is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol-2-ylaminocarbonyl.
More particularly, R7 is piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S); or
(b) R7 is xe2x80x94NHC(xe2x95x90O)OR14 where R14 is hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. Preferably, R7 is xe2x80x94NHC(xe2x95x90O)OR14 where R14 is hydrogen or xe2x80x94(C1-C12) alkyl, alkoxy, aryl, heteroaryl; or
(c) R7 is xe2x80x94(xe2x95x90O)OR14 where R14 is hydrogen, xe2x80x94(C1-C12) alkyl, substituted alkyl, or heteroalkyl, xe2x80x94(C1-C12) alkenyl, substituted alkenyl, or heteroalkenyl, xe2x80x94(C1-C12) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or xe2x80x94(C1-C8 alkyl or substituted alkyl)n9xe2x80x94(C3-C12 arylene or heteroarylene)-(C1-C8 alkyl or substituted alkyl)n10 where n9 and n10 are independently 0 or 1. Preferably, R7 is xe2x80x94(xe2x95x90O)OR17 where R14 is hydrogen or xe2x80x94C1-C12) alkyl, alkoxy, aryl, or heteroaryl. More preferably, xe2x80x94C(xe2x95x90O)OR14 where R14 is alkyl, even more preferably R7 is tert-butoxycarbonyl. The stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R7 group is either (R) or (S), preferably (S).
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-1,1-dimethylethyloxycarbonyl)-pyrrolidin-1-carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-pyridin-1-ylcarbonyl)pyrrolidin-1-carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-azetidin-1-ylcarbonyl)-pyrrolidin-1-carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-ethylaminocarbonyl)pyrrolidin-1-carbonyl)]-2-(S)-fluoropropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-phenylaminocarbonyl)-pyrrolidin-1-carbonyl)]-2-(S)-hydroxypropionamide;
N-hydroxy-3-[(S)-(n-butyl)-3-(2-(S)-pyrimidin-2-ylaminocarbonyl)pyrrolidin-1-carbonyl)]-2-(S)-hydroxypropionamide; and
N-hydroxy-3-[(S)-(n -butyl)-3-(2-(S)-thiazol-2-ylaminocarbonyl)-pyrrolidin-1-carbonyl)]-2-(S)-fluoropropionamide.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St. Louis, Miss., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Compounds of Formula (I) can be prepared by methods well known in the art of organic chemistry. Representative synthetic procedures for preparing compounds of the present invention are illusted and described in detail below. For example, compounds of Formula (I) can be prepared as described in Schemes A-D below.
A compound of Formula (I) where R1, R2, and R4 are hydrogen, and R3, R6, R7, Y, and n are as defined in the Summary of the Invention can be prepared as described in Scheme A below. 
Treatment of a solution of a mono-protected succinate of formula 1 where R is an alkyl group such as methyl, ethyl, and the like, and R3 is as defined in the Summary of the Invention, with an N,N-dialkylamine of formula 2, where R6 and R7 are as defined in the Summary of the Invention, provides a 3-aminocarbonyl-propionate derivative of formula 3. The reaction is typically carried out in the presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) in the presence of a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.). The reaction is initially started at low temperature, such as 0xc2x0 C., and then allowed to warm to room temperature, and then stirred for several hours. Some compounds of formula 1 are commercially available. Others can be prepared by methods well known in the art. For example mono-methyl succinate, mono-4-methyl-2-(R)-methylsuccinate is available commercially, while mono-4-methyl-2-(R)-butylsuccinate as described in detail in Example 16 below.
Amines of formula 2 are commercially available or they can be prepared by methods well known in the art. For example, N,N-dialkylamines such as pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine, homopiperazine, proline tert-butyl ester, L-proline-2-methylamide, (S)-(+)-2-(methoxymethyl)-pyrrolidine, L-proline-N-methoxy-N-methylamide, (S)-2-(pyrrolidinylmethyl)-pyrrolidine, L-proline-N-morpholineamide, L-proline-N,N-dimethylamide, homoproline methyl ester, L-homoproline tert-butylester, 3-(R)-tert-butoxy-L-proline-O-t-butyl ester, pipecolinic acid, 1,2,3,4-tetrahydroquinoline, 1-hydroxyethylpiperazine, 2-hydroxyethylpiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, 4-hydroxyproline, L-tetrahydroisoquinoline tert-butyl ester, 3-(N-Boc-amino)pyrrolidine, and N-Boc-L-prolinol are commerically available. Other N,N-dialkylamines 2 such as 2-acetylaminomethylpyrrolidine can be prepared from N-Boc-L-prolinol as described in Example 16 below. trans-3-Acetoxy-L-proline O-tert-butyl ester can be prepared from Cbz protected trans-3-hydroxy-L-proline as described in Example 17 below which can then be converted to trans 3-hydroxy-L-proline O-tert-butyl ester, if desired, by hydrolysis of the acetoxy group in trans-3-acetoxy-L-proline O-tert-butyl ester as described in Example 17 below.
Also, it will be recognized by a person skilled in the art that if compound 1 and/or 2 have additional reactive groups, then they must be suitably protected prior to carrying out the coupling reaction. Examples of suitable protecting groups and their introduction and removal are described in T. W. Greene and G. M. Wuts, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d Third Ed., Wiley, New York, 1999 and references cited therein. For example, if R6 or R7 is a carboxyl group or a hydroxy group then it can be protected as a t-butyl ester or benzyl ester or other suitable protecting group prior to the coupling reaction.
Compound 3 can optionally be converted to a compound of formula 4 where prior to converting it to a compound of Formula (I). This would be desirable if certain group(s) in compound 3, e.g., R3, R6, and/or R7 had to transformed to other group(s) within the scope of the invention prior to introducing the hydroxamate group in the molecule. For example, a compound of formula 3 where R6 or R7 is a tert-butoxyamino group, can be converted to a corresponding compound of formula 4 where R6 or R7 is an acetylamino group by first treating 3 with an acid such as diluted hydrochloric acid at ambient temperature to provide a corresponding compound of formula 3 where R6 or R7 is an amino group, followed by treatment with an acetylating agent such as acetic anhydride in the present of an organic base such as pyridine.
A compound of formula 3 where R6 and or R7 is a hydroxy can be converted to a compound of formula 4 where R6 and or R7 is a sulfonamido group (i.e., xe2x80x94NHSO2R15 where R15 is as defined in the Summary of the Invention) by first converting the hydroxy group into amino group, followed by treatment with a sulfonylating agent. A detailed description of this transformation is provided in Example 34 below.
A compound of formula 3 where R6 and or R7 is a suitably protected carboxyl group can be converted to a compound of formula 4 where R6 and or R7 is an aminocarbonyl group (i.e., xe2x80x94CONHR14 or xe2x80x94CONR14R15 where R14 and R15 is as defined in the Summary of the Invention) by first deprotecting the carboxy group and then treating with an amine of formula xe2x80x94NHR14 or xe2x80x94NR14R15 (where R14 and R15 is as defined in the Summary of the Invention). Briefly, the reaction conditions for deprotecting of the carboxy group will depend on the nature of the protecting group. For example, if it is a benzyl ester, then treatment with hydrogen gas and an appropriate catalyst (e.g., 10% palladium on carbon) will liberate the free carboxylic acid. The amination reaction is typically carried out in the presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) with a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.). The reaction is initially started at low temperature, such as 0xc2x0 C., and then allowed to warm to room temperature, and then stirred for several hours. Many amines of formulae NHR14 and NHR14R15 are available commercially, or can be readily prepared by methods well known in the art. For example, methylamine, aniline, 2-aminothiazole, etc., are commercially available. Others can be prepared, for example, via reductive amination of an aldehyde, or Fukuyama alkylation of a suitable nitroaryl sulfonamide followed by cleavage of the sulfonamide to liberate the desired amine.
Compound 3 or 4 is then converted to a hydroxamate compound of Formula (I) by treating it at 0xc2x0 C. with aqueous 50% hydroxylamine in a polar organic solvent such as dioxane and the like. After the reaction is complete the mixture is then purified by preparative reverse-phase (C18) HPLC to afford compound of Formula (I). If desirable, suitable O-protected hydroxylamine such as O-benzylhydroxylamine can also be used to give an O-protectedhydroxamate compound. Removal of the protecting group will provide a compound of Formula (I).
A compound of Formula (I) can be converted to other compounds of Formula (I) by methods well known in the art. Some such methods are described below. Compounds of Formula (I) containing a hydroxy group may be prepared by dealkylation/benzylation of an alkyloxy/benzyloxy substituent; and those containing an acid group, by hydrolysis of an ester group. Similarly, a compound of Formula (I) having an alkenyl or alkynyl group can be prepared by reacting a corresponding compound of Formula (I) containing a bromine or iodine atom with trimethylsilylacetylene under the Castro-Stephens reaction conditions. Furthermore, a compound of Formula (I) containing an alkoxy group may be prepared by alkylation of hydroxy substituent. A compound of Formula (I) containing a carboxy group can be prepared by hydrolyzing an ester group in a corresponding compound of Formula (I) under acid hydrolysis reaction conditions. The resulting carboxy group can optionally be converted to an amido group, if desired, by first converting the carboxy group to an activated ester derivative e.g., treating the carboxy compound with dicyclohexyl carbodiimide, DEAD and the like, followed by treatment with an amine. It will be recognized by a person skilled in the art that some of these transformations can be carried out prior to converting the compound of formula 5 to a compound of Formula (I).
A compound of Formula (I) where R1 is hydroxy, R2, and R4 are hydrogen, and R3, R6, R7, Y, and n are as defined in the Summary of the Invention can be prepared as described in Scheme B below. 
Treatment of dimethyl malate 5 under strongly basic conditions with an appropriate alkylhalide R3X (where R3 is alkyl, alkenyl, alkynyl, substituted, heteroalkyl and X is halo such as chloro, bromo, or iodo) provides 2-substituted dimethyl malate 6. The reaction is typically carried out in a polar aprotic solvent such as THF, and the base is typically lithium diisopropylamide (LDA). The reaction is initially carried out at a low temperature, preferably at about xe2x88x9278xc2x0 C., and then allowed to slowly warm to room temperature. The reaction is then stirred for several hours. The reaction is typically higher yielding when R3X is an allylic halide. After the alkylation is complete the resulting olefin can be reduced, if desired, to provide a compound of formula 6 where R3 is alkyl. The typically reduction procedure involves a suspension of 6 and a catalyst (e.g., 10% palladium on carbon) in a solvent such as ethylacetate and would be stirred under a hydrogen atmosphere for several hours to afford the corresponding compound of formula 6 where R3 is alkyl. Many compounds of formula R3X are commercially available or they can be prepared by methods well known in the art. For example, iodomethane, benzylbromide, crotylbromide, allylbromide, vinylbromide are commercially available. Others can be prepared from the corresponding alcohol by first activating the hydroxy group as a p-toluenesulfonate ester (tosyl ester), followed by tosylate displaced with a halide ion in a modified Finkelstein procedure to afford an alkylhalide as described in working examples below.
Treatment of 6 with a base affords a malic acid derivative of formula 7. The base can be an inorganic base such as lithium hydroxide or potassium hydroxide, and is most preferably sodium hydroxide. This reaction is usually performed in a polar, protic solvent such as methanol. Treatment of 7 with an orthoacetate, such as trimethylorthobenzoate, in the presence of an acidic catalyst affords an orthoester 8 (Ra is xe2x80x94Ph and Rb is xe2x80x94OMe). This reaction is ideally performed with a co-solvent, preferably in a mixture of toluene. The reaction is ideally performed at a higher temperature, most preferably at 110xc2x0 C. The catalyst is typically a sulfonic acid, such as p-toluenesulfonic acid, or most preferably camphorsulfonic acid.
Alternatively, treatment of 7 with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid provides an acetonide of formula 8 where Ra and Rb are methyl.
Treatment of the orthoester or acetonide 8 with a dialkylamine of formula 2 under the reaction conditions described in Scheme A provides a compound of formula 9 which upon treatment with a base, preferably the salt of an alcohol, and more preferably sodium methoxide in an alcoholic solvent then provides a 2-hydroxy-3-aminocarbonyl-propionate derivative of formula 10.
Compound 10 is then optionally converted to a compound of formula 11 for reasons discussed in Scheme A such as derivatizing the R3, R6 and/or R7 groups prior to converting it to a compound of Formula (I). Alternatively, compound 10 it can be directly converted to a compound of Formula (I) as described in Scheme A above.
It will be recognized by a person skilled in the art that the hydroxy group in compound 10 can be replaced by various other R1 groups as defined in the Summary of the Invention prior to converting it to a compound of Formula (I). Some representative examples are discussed below:
(i) the hydroxy group in compound 10 can be replaced by a fluoro group prior to converting it to a compound of Formula (I) as shown below. 
The hydroxyl group at the C2 carbon in compound 10 can be replaced by a fluoro group by first converting the hydroxyl group into an active ester followed by displaced with fluorine to afford compound 12. The reaction is performed in a halogenated solvent, such as dichloromethane (DCM), in the presence of an organic base, such as pyridine. The alcohol is typically activated as a sulfonate ester, preferably the trifluoromethane-sulfonate. This esterification reaction is typically carried out at a low temperature, preferably about xe2x88x9220xc2x0 C. The active ester is then reacted with a fluoride ion, typically derived from tris(dimethylamino)sulfur-(trimethylsilyl)difluoride (TAS-F). This reaction is also carried out at a low temperature, preferably at about xe2x88x9250xc2x0 C., and then slowly allowed to warm to ambient temperature. Compound 12 is then converted to a compound of Formula (I) either directly or through compound 13 as described above. A detailed description of this procedure is provided in Example 6 below. It will be noted that the stereochemistry at the C2 carbon atom is inverted during this transformation.
(ii) the hydroxy group in compound 10 can be converted to an alkoxy under alkylation reaction conditions such as treatment of 10 with an alkyl halide such as methyl iodide, ethyl iodide, benzyl bromide, and the like, in the presence of a strong base such as sodium hydride and in a polar solvent such as dimethylformamide. Detailed description of this procedure is provided in Example 45 below.
(iii) the hydroxy group in compound 10 can be converted to benzoyloxy group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with tetrabutyl ammonium benzoate. Detailed description of this procedure is provided in Example 47 below.
(iii) the hydroxy group in compound 10 can be converted to thiol group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment potassium thioacetate. Detailed description of this procedure is provided in Example 48 below.
(iv) the hydroxy group in compound 10 can be converted to an azido or amino group or it""s derivatives by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with sodium azide. The azide group can optionally reducted under catalytic hydrogenation reaction conditions to give an amino group which can be further derivatized by methods well known in the art. Detailed description of this procedure is provided in Example 49 and 34 below.
(vi) the maintainence of the stereochemistry at the carbon atom carrying the hydroxy group in compound 10, the C2 carbon, can be achieved by carrying out double inversion as illustrated and described below. 
The hydroxyl at the C-2 carbon of intermediate 10 is converted to an active ester as described above in (i) above. Nucleophilic substitution with a variety of nucleophiles such as acetate anion, or more preferably, tetrabutylammonium benzoate, provides intermediate 14. This reaction proceeds in a hydrocarbon solvent, preferably in toluene. One skilled in the art will understand that the above nucleophilic displacement reaction results in an inversion of stereochemistry at the C-2 position.
Compound 14 is treated with a base to afford hydroxy derivative 15. This base is preferably the salt of an alcohol such as sodium methoxide, sodium ethoxide and the like, and more preferably sodium methoxide. The reaction proceeds in an alcoholic solvent such as methanol, ethanol and the like, most preferably in methanol.
Compound 15 is re-activated as a sulfonate ester, preferably a trifluoromethane sulfonate as described above and then treated with a fluorination reagent, preferably TAS-F, to afford the corresponding fluoro intermediate 16 which has the same stereochemistry at the C-2 carbon as in intermediate 10.
Compound 16 or 17 is then converted to a compound of Formula (I) as discussed above.
A compound of Formula (I) can also be prepared as illustrated in Scheme C below. 
Treatment of a suspension of ArgoGel-Wang or ArgoGel-OH resin with an Fm-protected succinic acid of formula 19 (wherein R3 is as defined in the Summary of the Invention) in the presence of a coupling agent such as di-isopropylazodi-carboxylate and triphenylphosphine, followed by treatment with piperidine provides a resin bound Fm-protected succinic acid 20. The coupling reaction is carried out in a polar solvent such as dichloromethane in the presence of a base such as dimethylaminopyridine. The reaction is typically carried out at ambient temperature. Treatment of 20 with PFP-OTFA and pyridine, followed by treatment with an amine 2 then provides resin bound 3-aminocarbonylpropionate 21. The reaction is carried out in the presence of a non-nucleophilic base such as pyridine, diethylisopropylamine, 2,4,6-collidine, and the like. The reaction is typically carried out at ambient temperature. Treatment of 21 with hydroxylamine then provides a compound of Formula (I).
A compound of Formula (I) where R1 and R2 are fluoro and R2, R3, R6, R7, Y and n are as defined in summary of the invention can be prepared as illustrated in Scheme D below. 
Treatment of a compound of formula 8 with an alcohol such as tert-butanol in the presence of a suitable coupling agent such as DIC and a base such as DMAP provides the corresponding tert-butyl ester of formula 22. Treatment of 22 with a base such as sodium methoxide in methanol provides 2-hydroxysuccinate derivative of formula 23. Compound 23 is then converted to a trifluoromethanesulfonate ester derivative 24 using triflic anhydride in the presence of a base such as triethyamine, pyridine and the like. Treatment of 24 with a base such as triethylamine provides a maleic acid derivative of formula 25 which upon reaction with xenon difluoride in the presence of boron trifluoride etherate provides a 2,3-difluorosuccinate derivative. Removal of the tert-butyl group with trifluoroacetic acid provides the corresponding succinic acid derivative 26 which is then converted to a compound of Formula (I) as described above.
The present invention also provides pharmaceutical compositions which comprise a bioactive hydroxamic acid compound or derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compositions of the invention include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in animals, preferably mammals, more preferably humans.
The antibiotic compounds, also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics. Such methods are known in the art (see, e.g., Remington""s Pharmaceutical Sciences, Easton, Pa.: Mack Publishing Co.) and are not described in detail herein.
The composition can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical or parenteral. The compositions can be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. The compounds can also be administered in liposome formulations. The compounds can also be administered as prodrugs, where the prodrug administered undergoes biotransformation in the treated mammal to a form which is biologically active.
The topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, solutions, salves, emulsions, plasters, eye ointments and eye or ear drops, impregnated dressings and aerosols, and can contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations can also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers can be present, for example, from about 1% up to about 99% of the formulation. For example, they can form up to about 80% of the formulation.
Tablets and capsules for oral administration can be in unit dose presentation form, and can contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets can be coated according to methods well known in standard pharmaceutical practice.
Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection can be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions can contain, for example, from about 0.1% by weight to about 99% by weight, e.g., from about 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 1-500 mg of the active ingredient. The dosage as employed for adult human treatment will range, for example, from about 1 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 0.015 to 50 mg/kg per day. Suitably the dosage is, for example, from about 5 to 20 mg/kg per day.
The hydroxamate compounds of the present invention can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial or prokaryotic organisms. Examples include Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphylococci, for example S. aureus and S. epidermidis; Enterococci, for example E. faecalis and E. faecium; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli. Other examples include Mycobacteria, for example M. tuberculosis; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example M. pneumoniae. 
In one embodiment, compositions, for treating or preventing infectious disorders are provided, comprising a hydroxamic acid compound or derivative as disclosed herein in combination with a pharmaceutically acceptable carrier.
In another embodiment, there is provided a dosage amount of a hydroxamic acid compound or derivative as disclosed herein in an effective amount for the treatment, prevention or alleviation of a disorder, such as an infectious disorder.
Hydroxamic acid compounds or derivatives can be screened for activity against different microbial agents and appropriate dosages can be determined using methods available in the art. The compounds can be used to treat a subject to treat, prevent, or reduce the severity of an infection. Subjects include animals, plants, blood products, cultures and surfaces such as those of medical or research equipment, such as glass, needles, surgical equipment and tubing, and objects intended for temporary or permanent implantation into an organism. Treating a subject includes, but is not limited to, preventing, reducing, or eliminating the clinical symptoms caused by an infection of a subject by a microorganism; preventing, reducing, or eliminating an infection of a subject by a microorganism; or preventing, reducing, or eliminating contamination of a subject by a microorganism. The microorganism involved is preferably a prokaryote, more preferably a bacterium.
In one embodiment, methods of treating or preventing an infectious disorder in a subject, such as a human or other animal subject, are provided, by administering an effective amount of a hydroxamic acid compound or derivative as disclosed herein to the subject. In one embodiment, the compound is administered in a pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier. As used herein, an xe2x80x9cinfectious disorderxe2x80x9d is any disorder characterized by the presence of a microbial infection, such as the presence of bacteria. Such infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. The compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically. Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, nasal, vaginal, rectal, and oral administration. The specific dosage of antimicrobial to be administered, as well as the duration of treatment, can be adjusted as needed.
Additionally, the compounds of this invention can also be used to prepare a composition in an inert diluent which is useful in inhibiting bacterial growth. An xe2x80x9cinert diluentxe2x80x9d means an excipient that is useful in preparing a composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable.
Representative pharmaceutical formulations containing a compound of Formula (I) are described below.
The ability of the compounds of this invention to inhibit peptide deformylase was measured by in vitro assay described in detail in Biological Example below. The antimicrobial activity of the compounds of this invention was tested as described in detail in Biological Example 2 below. The selective inhibition of PDF compared to MMP-7 (Matrilysin) by the compounds of this invention was tested as described in detail in Biological Example 3 below.